ES2935800T3 - Ketamine Oral Dosage Form - Google Patents

Abstract

The present invention relates to an oral dosage form for the administration of ketamine and to a method of preparing an oral dosage form for the administration of ketamine, preferably once or twice a day. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Ketamine Oral Dosage Form

The present invention relates to an oral dosage form of ketamine.

The dosage form can be used in the treatment of neuropathic pain, preferably once or twice daily.

Ketamine is a drug used in human and veterinary medicine, mainly for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include intensive care sedation, analgesia, and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation. Like other drugs in its class, such as tiletamine and phencyclidine (PCP), ketamine induces a state called "dissociative anesthesia" and is used as a recreational drug. Ketamine hydrochloride is marketed as Ketanest®, Ketaset®, and Ketalar®. Pharmacologically, ketamine is classified as an N-methyl-D-aspartate (NMDA) receptor antagonist.

Ketamine may be effective in treating depression in patients with depression and bipolar disorder who have not responded to antidepressants. It produces a rapid antidepressant effect, as opposed to the several weeks it takes for typical antidepressants to work.

Ketamine may also be effective in the treatment of neuropathic pain. Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, and pain produced by normally non-painful stimuli (allodynia). Neuropathic pain can have continuous and/or episodic (paroxysmal) components.

Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes and other metabolic states, common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancy, immune-mediated disorders, and physical trauma to a trunk. highly strung. Neuropathic pain is common in cancer as a direct result of peripheral nerve cancer (for example, compression by a tumor), or as a side effect of chemotherapy, radiation injury, or surgery.

At subanesthetic doses, ketamine produces a dissociative state, characterized by a feeling of detachment from one's own body and from the external world known as depersonalization and derealization. At sufficiently high doses, users can experience what is called the "K hole", a state of extreme dissociation with visual and auditory hallucinations.

A problem associated with analgesics and opioid analgesics is the so-called rapid absorption of the dose. Dose-rapid absorption is a phenomenon that occurs, for example, when patients do not adhere to advice to avoid alcohol intake concomitantly with administration of the controlled-release pharmaceutical dosage form. The intake of alcohol can drastically accelerate the release of the active substance, thus leading to potentially very harmful consequences for the patient, in particular in the case of analgesics and opioid analgesics. In addition, the accelerated release of the active principle by means of alcohol for example is often also a process desired by people seeking a hallucinogenic experience caused by a high dose of the drug, thus leading to drug addiction.

Therefore, it is desirable to provide dosage forms that can minimize dose rapid absorption and drug addiction.

Furthermore, the possibility of forming controlled release dosage forms of ketamine is described in the prior art. However, no specific controlled release composition or formulation comprising ketamine is known in the prior art. EP 1103256 A1 describes the use of ketamine in the treatment of neuroendocrine immune dysfunction or algogenic psychosyndrome. Ketamine can be administered orally, for example, as a controlled release dosage form. WO 2008/134525 A1 relates to deuterium-labelled ketamine and pharmaceutical compositions thereof, also comprising release control agents. DE 10 2007 009 888 A1 describes the use of S-(+)-ketamine to treat depression. Among others, its oral administration is disclosed, without specifying the composition or addressing the problem of rapid absorption of the dose and/or the problem of drug addiction. WO 2008/086804 discloses compositions that have been shown to mitigate the risk of alcohol-induced dose-rapid absorption.

No specific controlled release composition or formulation comprising ketamine is disclosed in the prior art and no ketamine controlled release formulation has been marketed, but only ketamine formulations for parenteral administration, such as Ketanest, Ketaset and Ketalar, since they do not A satisfactory in vivo plasma level of ketamine could be achieved with oral formulations.

Therefore, an object of the present invention is to provide an oral dosage form of ketamine which provides a satisfactory in vivo plasma level of ketamine and at the same time prevents dose rapid absorption and drug addiction.

The inventors of the present invention have now surprisingly found that very advantageous in vivo properties can be achieved by an oral dosage form comprising ketamine, which provides a specific in vitro release of ketamine.

Therefore, one aspect of the present invention is the provision of an oral dosage form comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, according to claim 1. In a first embodiment of the invention the dosage form provides a in vitro release of ketamine 0-40% after 2 hours, 10-70% after 4 hours, 30-85% after 6 hours, and 45-100% after 8 hours, when measured by basket method I of USP in 0.1 M HCl at 100 rpm and 37 °C.

In a preferred embodiment, the in vitro release of ketamine is 5 to 30%, preferably 8 to 25% after 2 hours, 20 to 60% after 4 hours, 45 to 80% after 6 hours, and 60 to 99%. % after 8 hours, when measured according to USP Basket Method I in 0.1 M HCl at 100 rpm and 37°C.

According to the invention there is provided a modified release oral dosage form comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the ratio of the amount of ketamine released after 1 hour of in vitro dissolution of the dosage form at 37°C in an aqueous solution containing 20% by volume of ethanol based on the amount of ketamine released after 1 hour of in vitro dissolution of the dosage form at 37°C in an ethanol-free aqueous solution is less 2:1, preferably less than 1.7:1, more preferably less than 1.5:1, most preferably less than 1.2:1, when measured according to USP Basket Method 1 in 0 HCl .1M at 100rpm.

Therefore, the dosage forms of the present invention have proven to be advantageous in avoiding the effect of so-called rapid absorption of the dose. The use of the dosage forms of the present invention has been found to be a very effective means of avoiding or at least significantly reducing the risk of dose rapid absorption following alcohol ingestion.

As used herein for all in vitro release measurements, USP Basket Method I is performed in 500 mL of fluid for amounts of ketamine less than or equal to 10 mg and in 1000 mL of liquid for amounts of ketamine greater than 10 mg. If ketamine is used as the free base, the amount of 10 mg refers to the weight of the free base. If ketamine is used in the form of a pharmaceutically acceptable salt or solvate, the amount of 10 mg refers to the weight of the salt or solvate.

"Ketamine" as used herein is understood to comprise the compound of formula (I)

which has the IUPAC name 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Accordingly, ketamine comprises the R and S enantiomers as well as pharmaceutically acceptable salts or solvates thereof. In one embodiment, the ketamine is (R)-ketamine or pharmaceutically acceptable salts or solvates thereof. In another embodiment, the ketamine is (S)-ketamine or pharmaceutically acceptable salts or solvates thereof. In a further embodiment, ketamine is a racemate of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts. acceptable or solvates thereof. Ketamine may preferably comprise pharmaceutically acceptable acid addition salts thereof. The acids that are used to prepare the pharmaceutically acceptable acid addition salts are preferably those that form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate. , phosphate, acid phosphate, acetate, lactate, citrate, (D,L)- and L-tartrate, (D,L)- and L-malate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, and benzoate. A preferred salt is ketamine hydrochloride.

Ketamine as used herein may also comprise its metabolites. The metabolite is norketamine or dehydronorketamine, preferably norketamine. Norketamine has the IUPAC name 2-amino-2-(2-chlorophenyl)cyclohexan-1-one of formula (II)

and is obtained from ketamine through N-demethylation. Norketamine may be provided as (R)-norketamine or pharmaceutically acceptable salts or solvates thereof, or (S)-norketamine or pharmaceutically acceptable salts or solvates thereof, (S)-norketamine and (R)-norketamine racemate or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-norketamine and (R)-norketamine or pharmaceutically acceptable salts or solvates thereof. Dehydronorketamine has the IUPAC name 6-amino-6-(2-chlorophenyl)cyclohex-2-en-1-one of formula (III)

Dehydronorketamine may be provided as (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, or (S)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, racemate of (S)-dehydronorketamine and (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-dehydronorketamine and (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof. Norketamine and dehydronorketamine may preferably comprise the pharmaceutically acceptable acid addition salts thereof. The acids that are used to prepare the pharmaceutically acceptable acid addition salts are preferably those that form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate. , phosphate, acid phosphate, acetate, lactate, citrate, (D,L)- and L-tartrate, (D,L)- and L-malate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, and benzoate. A preferred salt is the hydrochloride salt.

The following description of embodiments applies to both aspects of the invention. Furthermore, the first aspect and the second aspect of the invention are not mutually exclusive, ie embodiments of the first aspect can simultaneously comprise features of the first aspect and vice versa.

The oral dosage form of the present invention is a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or site of release of the active ingredient is different from that of an immediate dosage form when administered by means of the same way. Modified release dosage forms can include delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated and rapid release, targeted, programmed and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate delivery devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. Matrix and multiparticulate controlled release dosage forms are according to the invention.

According to the invention, the dosage form comprises a non-erodible matrix system. Ketamine can be dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix after administration.

Preferred materials for forming a matrix include chitin, chitosan, dextran and pullulan, gum agar, gum acacia, karaya gum, locust bean gum, gum tragacanth, carrageenan, ghatti gum, guar gum, xanthan gum and scleroglucan, starches, such as dextrin and maltodextrin, hydrophilic colloids such as pectin, phosphatides such as lecithin, alginates, propylene glycol alginate, gelatin, collagen and cellulosic materials such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC) , hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), Cellulose Butyrate (CB), Cellulose Acetate Butyrate (CAB), Cellulose Acetate Phthalate (CAP), Cellulose Acetate Trimellitate (CAT), Hydroxypropyl Methylcellulose (HPMC), HPMCP, HPMCAS, Hydroxypropyl Methylcellulose Acetate Trimellitate (HPMCAT) ) and ethylhydroxyethylcellulose (EHEC), polyvinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetate), fatty acid esters, polyacrylamide, poly(acrylic acid), ethacrylic acid or methacrylic acid copolymers (EUDRAGIT®, Rohm America, Inc ., Piscataway, NJ), poly(2-hydroxyethyl methacrylate), polylactides, copolymers of L-glutamic acid and ethyl L-glutamate, degradable lactic acid-glycolic acid copolymers, poly-D-(-)-3 acid -hydroxybutyric, and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

Additional materials for forming a matrix device include plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, poly(methyl methacrylate), poly(butyl methacrylate), chlorinated polyethylene, poly(vinyl chloride), copolymers of methyl acrylate-methyl methacrylate, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride-vinyl acetate copolymers, vinylidene chloride, ethylene and propylene, poly ionomer (ethylene terephthalate), butyl rubber, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, poly (ethylene terephthalate) plasticized, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides such as hydrogenated castor oil. In a preferred embodiment the matrix-forming material is hydrogenated castor oil. In another preferred embodiment, the material that forms the matrix is HpMC.

The matrix-forming material is preferably present in the dosage form of the invention in a concentration of between 10 and 95% by weight, more preferably between 20 and 75%, in particular between 25 and 65%. , based on the total weight of the dosage form.

The dosage form comprising a matrix system may further comprise excipients such as lubricants, fillers, glidants, binders, stabilizers. With regard to preferred embodiments of said excipients, reference is made to the explanations given below.

In a preferred embodiment the dosage form comprises 10 to 95% by weight, more preferably 20 to 75%, in particular 30 to 65% of matrix-forming material, 0 to 90% by weight, preferably 5 to 70% by weight, more preferably 10 to 50% by weight, in particular 15 to 30% by weight of fillers, optionally 0 to 25% by weight, preferably 1 to 20% by weight, more preferably 5 to 15% binders, 0 to 5% by weight, preferably 0.1 to 4% by weight, more preferably 0.5 to 3% glidants, 0 to 5% by weight, preferably 0.1 3% by weight, more preferably 0.3 to 2% lubricants based on the total weight of the dosage form.

The matrix controlled release dosage form can be prepared by direct compression, wet granulation, or dry granulation. Direct compression is a preferred embodiment. For more detailed explanations on the compression stage, refer to the illustrations provided below. It is also according to the invention that the dosage form is a multiparticulate dosage form and comprises a multitude of particles. The granules contain a core comprising ketamine and a release control layer coated on the core. Preferably, the release control layer is (physically) separated from the ketamine-containing core. The ketamine-containing core may be a ketamine-containing core and excipients. In those embodiments, the excipients preferably do not slow or substantially delay the release of the ketamine.

Preferably, the core comprises a layer of ketamine on an inert core. The inert core (also called seed core or neutral bead) may be granules or beads, preferably spherical, and further preferably made of sugar or cellulose or other suitable materials. By way of example, mention may be made of sucrose-based inert spherical nuclei, such as those commercially available under the trade name Suglets® or those based on cellulose, such as those commercially available under the trade name Celphere® or Cellets®. Inert sucrose-based nuclei are particularly preferred. The inert nuclei may preferably have a particle size in the range of 100 to 500 |im and more preferably in the range of 200 to 400 |im, the particle size range indicating the size range for 90% of the particles. as determined by sieve analysis.

Preferably, the ketamine is provided by coating a layer of ketamine-containing directly onto the inert cores. The ketamine-containing layer preferably does not retard the release of ketamine, ie it is an immediate release layer.

In one embodiment, each pellet contains a core comprising ketamine and a release control layer coated on the core. In an alternative embodiment, granules containing ketamine nuclei and a release control layer coated on the nuclei can be mixed with other granules.

In one embodiment of the invention, the core does not comprise a neutral bead as described above, but rather a bead comprising ketamine and optionally at least one pharmaceutically acceptable excipient. The ketamine-containing bead can be formed by dry granulation, wet granulation, spray granulation or extrusion.

Preferably, a suitable ketamine-containing core comprises 10 to 50% by weight, preferably 15 to 40% by weight, more preferably 20 to 30% by weight inert core (neutral bead), 20 to 90% by weight , preferably from 35 to 80% by weight, more preferably from 50 to 70% by weight of ketamine, in particular ketamine hydrochloride, from 0.1 to 20% by weight, preferably from 1 to 15% by weight, more preferably from 3 to 10% by weight of binder, and optionally 0 to 20% by weight, preferably 1 to 15% by weight, more preferably 3 to 10% by weight of glidant, based on the total weight of the ketamine-containing core . Binders generally serve to enhance tablet integrity and stability. In addition, they can improve the suitability of pharmaceutical compositions for granulation. Film-making binders, such as active agent-containing layers around an inert core, are also commonly used. Exemplary binders include synthetic polymers, such as polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer, modified celluloses, such as hydroxyalkylcelluloses, and mixtures thereof. A binder is typically used in an amount of 0 to 25% by weight, preferably 0.1 to 15% by weight and in further embodiments 1 to 10% by weight of the controlled release oral dosage form. Preferably, hypromellose (HPMC) or PVP is used as a binder in the ketamine-containing core, more preferably HPMC. Preferably said HPMC has a methoxy content of 20% to 40%, more preferably 25% to 35%. Furthermore, preferably said HPMC has a hydroxypropoxyl content of about 5% to 15%, more preferably 7% to 12%. Preferably, a 2% by weight (aqueous) solution of said HPMC has a viscosity of 0.5 to 100 mPâ s, preferably 1 to 50 mPâ s, more preferably 2 to 10 mPâ s, measured at 20 °C, preferably by means of a Brookfield-Synchro-Lectric LVF viscometer. Preferably, the PVP has an average molecular weight of 1,000 to 2,500,000, preferably 5,000 to 2,000,000, more preferably 10,000 to 1,500,000.

Generally, glidants such as dispersed silica, such as Aerosil®, or talc can be used. In particular, talc is used as a glidant in the ketamine-containing core.

In one embodiment, the ketamine-containing core does not comprise a glidant.

The release control layer can be arranged in the direct vicinity, ie in immediate contact with and surrounding the ketamine-containing core, which is preferred. In other exemplary embodiments, an intermediate layer may be provided between the ketamine-containing core and the release control layer. This intermediate layer can further control the release of ketamine from the nucleus. However, it is preferred that, if present, the interlayer does not substantially influence the release of the core.

The release control layer comprises a release control substance to control the release of ketamine from the granules. The release control substance can be any substance known in the art to be suitable for controlling the release of an active substance. Exemplary embodiments of suitable control release substances include cellulose esters, such as cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethylene oxide, polylactide-co-glycolide, and mixtures thereof. Suitable additional polymers include those selected from alkyl celluloses, in particular cellulose ethers, acrylate or methacrylate based polymers and copolymers, acrylic or methacrylic ester based polymers and copolymers and mixtures thereof. Preferably, the release control substance is a water-insoluble polymer, preferably an alkylcellulose. More preferably, the alkylcellulose is ethylcellulose.

In exemplary embodiments of the present invention where the release control substance is a polymer, said polymer has a weight average molecular weight of 5,000 to 500,000 g/mol, preferably 50,000 to 900,000 g/mol, more preferably from 100,000 to 400,000 g/mol, for example from 140,000 to 300,000 g/mol. The weight average molecular weight is preferably determined by gel permeation chromatography.

In further embodiments, and in addition to or as an alternative to one or more of the aforementioned properties, the release control substance, and in particular the polymer, preferably has a water solubility of less than 20 mg/l, preferably less than 15 mg/l. mg/l, preferably between 0.001 and 10.0 mg/l. The solubility in water is preferably determined according to European Regulation RL67-548 EWG, Annex V, Chapter A6 (German version to which reference is made herein).

In further embodiments, when a polymer is used as or as part of the release control substance, and in addition to or as an alternative to one or more of the aforementioned properties, the polymer has a glass transition temperature of 20 to 220° C, for example, from 60 to 150 °C or from 90 to 140 °C. The glass transition temperature is preferably measured by means of DSC differential scanning calorimetry, preferably using a Mettler Toledo instrument and preferably applying a heating/cooling rate of 10°C per minute.

In a particularly preferred embodiment, the release control substance is ethylcellulose having an ethoxy content of about 30-70%, more preferred about 40-60%. Preferably, a 2% by weight (aqueous) solution of ethylcellulose has a viscosity of 5 to 500 mPâ s, preferably 10 to 100 mPâ s, measured at 25 °C, preferably by means of a Brookfield-Synchro-Lectric LVF viscometer. .

In exemplary embodiments, the release control substance is contained in an amount of 0.1 to 80% by weight of the total weight of the granules in the dosage form, more preferably in amounts of 0.5 to 60%. % by weight, from 10 to 50% by weight, from 15 to 40% by weight, of the total weight of the granules in the dosage form.

Release rate control can be tailored by appropriate selection of the release control substance or mixture of such substances, their amount, coating thickness, inclusion of additional excipients, such as pore formers and/or plasticizers or others. .

In addition to the release control substance, one or more additional excipients may be used, in particular in a release control layer. A preferred excipient for use with the release control substance, in particular a polymeric release control substance, is a plasticizer and/or a glidant and/or pore former.

A plasticizer, as the term is used herein, is a substance that normally lowers the glass transition temperature of the polymer used in the blend by at least 2°C, preferably at least 5°C, for example between 5 and 30 °C, compared to the polymer alone. Preferably, the plasticizer is triethyl citrate or propylene glycol.

A pore former is usually a substance that has a water solubility that is greater than the water solubility of the release control substance. Preferably, the pore former has a water solubility of more than 20 mg/l, preferably 50 mg/l to 5000 mg/l, more preferably 100 to 1000 mg/l. Water solubility is preferably determined as described above. In particular, hydroxypropyl cellulose (HPC) is used as a pore former.

In a preferred embodiment, the release control layer comprises 20 to 95% by weight, preferably 40 to 80% by weight, more preferably 50 to 70% by weight of release control substance, preferably such as as described above, 0.1 to 30% by weight, preferably 1 to 25% by weight, more preferably 5 to 20% by weight of pore former, preferably as described above, 0.1 to 30 % by weight, preferably 1 to 25% by weight, more preferably 5 to 20% by weight of plasticizer, preferably as described above, and optionally 0 to 40% by weight, preferably 3 to 30% by weight , more preferably 5 to 20% by weight of glidant, preferably as described above, based on the total weight of the release control layer.

The release control layer may be a single layer or a plurality of layers. For ease of manufacture, embodiments with a single release control layer are preferred.

The granules can be used as a pharmaceutical formulation, for example, without any further processing. For this type of administration, the granules are preferably filled into sachets. In the alternative, they may be incorporated into capsules, optionally together with one or more excipients, or in other suitable ingestible pharmaceutical dosage forms.

Most preferably, the granules are contained in an external phase of at least one pharmaceutically acceptable excipient. Furthermore, the controlled release oral dosage form is preferably a tablet.

As is evident from what has been stated above, most preferably, the oral dosage form according to the present invention does not contain any ketamine in immediate release form, i.e. it does not contain ketamine, the release of which is not controlled by the Release control substance(s). For example, a tablet comprising the plurality of controlled release ketamine granules does not comprise any additional ketamine in the external phase as a top coat on the tablet.

In particularly preferred embodiments, the granules are mixed in a so-called "external phase" in order to be compressed into tablets. The external phase must guarantee the stability of the granules during compression and is usually made up of one or more pharmaceutically acceptable excipients, such as fillers, binders, disintegrants, glidants and lubricants.

Typically fillers are used to dilute a pharmaceutical composition and provide bulk. Examples of preferred fillers include lactose, starch, calcium phosphate, calcium carbonate, sucrose, sugar alcohols such as mannitol, sorbitol, xylitol, and celluloses and derivatives. Microcrystalline cellulose is particularly preferred. In a preferred embodiment, a filler mixture comprising sodium carboxymethylcellulose and cellulose is used. microcrystalline, preferably in a weight ratio of 5:1 to 1:5, more preferably 3:1 to 1:3. A filler or mixture of fillers can be used in an amount of 0 to 80% by weight, preferably 1 to 70% by weight, based on the total weight of the controlled release oral dosage form, preferably the tablet. Binders generally serve to enhance tablet integrity and stability. In addition, they can improve the suitability of pharmaceutical compositions for granulation. Binders are also commonly used for the preparation of films, such as active agent-containing layers around an inert core. Exemplary binders include synthetic polymers, such as polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, modified celluloses, such as hydroxyalkylcelluloses, and mixtures thereof. A binder is normally used in an amount of 0 to 30% by weight, preferably 0.1 to 15% by weight and in further embodiments 1 to 10% by weight of the controlled release oral dosage form. Preferably, hypromellose (HPMC) is used as a binder.

A disintegrant enhances the disintegration of a dosage form, particularly a tablet, upon immersion in water or gastric juices. Suitable disintegrants include carrageenan, starches, croscarmellose, crospovidone, and mixtures thereof. Disintegrants may be used in amounts of 0 to 25% by weight, preferably 1 to 20% by weight and in further embodiments 3 to 15% by weight of the controlled release oral dosage form, preferably the tablet.

Oral dosage forms may further include a glidant, such as dispersed silica, such as Aerosil®, or talc. A glidant (or mixture thereof) may be comprised in an amount of 0 to 5% by weight, for example 0.1 to 4% by weight of the controlled release oral dosage form, preferably the tablet.

The controlled release oral dosage form may further comprise a lubricant, particularly in tablets made by compression. Suitable lubricants include stearic acid, magnesium stearate, adipic acid, and sodium stearyl fumarate (Pruv®).

Preferably, the amount of granules in the controlled release oral dosage form ranges from 1% to 100% by weight, based on the total weight of the controlled release dosage form. In preferred embodiments, the granules are comprised in an amount of 20% to 90% by weight, more preferably 25% to 80% by weight, based on the total weight of the controlled release dosage form.

In a preferred embodiment, the external phase (without coated cores) comprises from 85 to 99.9%, preferably from 90 to 98% by weight of filler, from 0 to 5%, preferably from 0.1 to 1.0% by weight. of lubricant and 0.1 to 10%, preferably 1.0 to 5% by weight of glidant, based on the total weight of the external phase.

Optionally, the oral dosage form according to the present invention, particularly when present in the form of a tablet, may comprise an outer film for improved ease of swallowing, for protection, for colouring, for taste masking or other purposes. Preferably, this outer film does not influence ketamine release to any significant degree. The external film can comprise the usual excipients known in this art for this purpose. A combination of hypromellose, talc, a coloring agent, such as titanium dioxide, and/or a polymer, such as polyethylene glycol, is a preferred embodiment herein. Preferably off-the-shelf products such as Opadry® based on hypromellose or poly(vinyl alcohol) are used for film coating. This optional film is not counted in the total weight of the controlled release oral dosage form herein. Stated another way, any amount of a component expressed as a percentage by weight herein refers to the controlled release oral dosage form without this optional outer film. As is evident from the above, the outer film is free of ketamine in any form.

The oral dosage form according to the present invention has the advantage that it can be divided into two or more units without disturbing the controlled release of ketamine. The controlled release oral dosage form, and in particular the tablet, can therefore comprise means that facilitate its division into two or more units, such as a break line, each of said units providing the controlled release of ketamine. The dosage form according to the present invention thus provides the possibility to adjust the dosage, for example halving the dosage by breaking the tablet in two.

In preferred embodiments according to the present invention, the ketamine salt is ketamine hydrochloride. The dosage form may contain ketamine in amounts of 5 to 400 mg, preferably 5 to 200 mg. If ketamine is used as the free base, the amount from 5 to 400 mg refers to the weight of the free base. If ketamine is used in the form of a pharmaceutically acceptable salt, the amount from 5 to 400 mg refers to the weight of the salt. Preferably, the dosage form of the present invention comprises ketamine 10mg, ketamine 20mg, ketamine 40mg, ketamine 80mg, ketamine 100mg, ketamine 120mg, ketamine 140mg, ketamine 160mg , ketamine 180mg, ketamine 200mg, ketamine 220mg, ketamine 240mg, ketamine 260mg, ketamine 280mg, ketamine 300mg, ketamine 320mg, ketamine 340mg, ketamine 360mg , 380 mg of ketamine, more preferably 10 mg of ketamine hydrochloride, 20 mg of ketamine hydrochloride, 40 mg of ketamine hydrochloride, 80 mg of ketamine hydrochloride, 100 mg of ketamine hydrochloride, 120 mg of Ketamine Hydrochloride, Ketamine Hydrochloride 140mg, Ketamine Hydrochloride 160mg, Ketamine Hydrochloride 180mg, Ketamine Hydrochloride 200mg, Ketamine Hydrochloride 220mg, Ketamine Hydrochloride 240mg, Hydrochloride 260mg Ketamine Hydrochloride 280mg Ketamine Hydrochloride 300mg Ketamine Hydrochloride 320mg Ketamine Hydrochloride 340mg Ketamine Hydrochloride 360mg Ketamine Hydrochloride 380mg

It is further preferred that the dosage form of the present invention comprises:

i) ketamine-containing cores comprising

1 to 30% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight of inert nuclei,

1 to 40% by weight, preferably 5 to 20% by weight, more preferably 10 to 15% by weight of ketamine, in particular ketamine hydrochloride,

0.01 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight of binder, and 0 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight of glidant,

ii) a release control layer coated on each ketamine-containing core, comprising 1 to 40% by weight, preferably 3 to 20% by weight, more preferably 7 to 15% by weight of release control substance. the Liberation,

0.01 to 10% by weight, preferably 0.1 to 6% by weight, more preferably 1 to 4% by weight of pore former,

0 to 10% by weight, preferably 0.1 to 6% by weight, more preferably 1 to 4% by weight of plasticizer,

0 to 15% by weight, preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight of glidant,

and

iii) an external phase comprising

20 to 85%, preferably 40 to 75%, more preferably 50 to 65% load,

0 to 3% by weight, preferably 0.001 to 2.0% by weight, more preferably 0.1 to 0.5% by weight of lubricant and

0 to 5% by weight, preferably 0.1 to 5% by weight, more preferably 0.5 to 2.0% by weight of glidant,

wherein all wt% are based on the total weight of the tablet (without film coating).

The tablets of the present invention preferably have a tablet height of 2 to 8 mm, more preferably 3 to 5 mm, and a length of 3 to 22 mm, preferably 5 to 17 mm. Preferably the tablets have a hardness of 40 to 300 N, more preferably 50 to 200 N.

In a further embodiment of the invention, administration of a single oral dosage form leads in vivo to a Cmax. of ketamine 1 to 150 ng/ml, preferably 2 to 120 ng/ml, more preferably 3 to 100 ng/ml, still more preferably 4 to 70 ng/ml, further more preferably 5 to 40 ng/ml , and to an AUC0-» of 5 to 1000 hng/ml, preferably 10 to 750 hng/ml, more preferably 50 to 600 hng/ml, still more preferably 100 to 400 hng/ml.

In a further embodiment, administration of a single oral dosage form leads to a Cmax in vivo . norketamine 5 to 750 ng/ml, preferably 10 to 600 ng/ml, more preferably 15 to 500 ng/ml, still more preferably 20 to 400 ng/ml, further more preferably 25 to 300 ng/ml , and to an AUC0-» of 100 to 8000 hng/ml, preferably 150 to 6000 hng/ml, more preferably 500 to 4000 hng/ml.

“Cmax.” means the peak concentration of ketamine in the plasma, for example determined as described below. "AUC ^ü -~" describes the bioavailability of ketamine and is measured by calculating the area under the curve (AUC) of the time profile of plasma drug concentration from time zero extrapolated to infinity.

In a further preferred embodiment of the invention, the Tmax. of ketamine is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h.

In a further preferred embodiment of the invention, the Tmax. of norketamine is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h.

“Tmax.” means the time from administration to reaching Cmax.

In a further preferred embodiment of the invention, the oral dosage form has a Fabs of 5 to 25%, preferably 7 to 20%, more preferably 9 to 18%.

“Fabs” is the absolute bioavailability. Absolute bioavailability compares the bioavailability of the active drug in the systemic circulation after non-intravenous administration (ie, after oral administration in the present case), with the bioavailability of the same drug after intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared to the corresponding intravenous administration of the same drug. Absolute bioavailability is the area under the curve (AUC) corrected for the non-intravenous (oral) dose divided by the intravenous AUC. For example, the formula to calculate Fabs for an orally administered drug is given below:

Fabs _ AUCoral / AUCiv x doseiv / dose oral

The controlled release oral dosage forms according to the present invention are preferably for use in the treatment of severe and very severe pain, more preferably severe and very severe pain corresponding to a value between 6 and 10 on the visual analogue scale ( VAS) of pain distress numerical scale from 1 to 10. In particular, the controlled-release oral dosage form is suitable for patients who need continuous treatment for a long period of time.

The controlled release oral dosage forms according to the present invention are for use in the treatment of neuropathic pain. As described above, neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes and other metabolic states, common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancy, immune-mediated disorders, and physical trauma to a trunk. highly strung. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (for example, compression by a tumor), or as a side effect of chemotherapy, radiation injury, or surgery.

Accordingly, the oral dosage form of the present invention is for use in the treatment of patients suffering from spinal cord injury, multiple sclerosis, cancer, immune-mediated disorders, metabolic states such as diabetes, herpes infection zoster, HIV-related neuropathies, nutritional deficiencies.

Furthermore, the present invention provides, but does not claim, a method for treating severe and very severe pain, more preferably severe and very severe pain corresponding to a value between 6 and 10 on the visual analogue numerical scale (VAS) scale. numerical pain distress from 1 to 10, using an oral dosage form of ketamine as described above.

In a further embodiment, an oral dosage form is provided for use in a method of treating depression in patients with depression and bipolar disorder who have not responded to antidepressants.

Still further, an oral dosage form is provided for use in a method of treating neuropathic pain using an oral dosage form of ketamine as described above.

In one embodiment of the invention, an oral dosage form is provided for use in a method of treating patients suffering from spinal cord injury, multiple sclerosis, cancer, immune-mediated disorders, metabolic states such as such as diabetes, herpes zoster infection, HIV-related neuropathies, nutritional deficiencies using the oral dosage form of the present invention. The oral dosage form of the present invention is administered once or twice a day, preferably twice a day.

According to a further aspect, not claimed, there is provided a method of preparing an oral dosage form, preferably as described above, comprising:

a) coating each inert core with a layer comprising ketamine or a pharmaceutically acceptable salt or solvent thereof,

b) coating each coated inert core with a release control layer comprising a release control substance for controlling the release of ketamine, thereby forming granules,

c) mixing the granules with at least one pharmaceutically acceptable excipient,

d) forming a tablet from the mixture comprising the granules and the at least one pharmaceutically acceptable excipient.

For preferred embodiments of inert cores, preferred ketamine forms, release control substances, additional excipients, the granules etc., reference is made to the explanations concerning the embodiments of the dosage forms of the present invention above, which naturally refer to they equally apply to the method of preparing a controlled release dosage form according to the present invention.

Step a) may further include dissolving or suspending ketamine or a salt thereof in a suitable solvent or mixture of solvents, optionally together with a binder, such as a hydroxyalkylcellulose, such as hydroxypropylmethylcellulose. The solvent is preferably water, an alcohol, such as ethanol, or mixtures thereof.

Preferably, the inert nuclei are sugar spheres. Preferably, ketamine hydrochloride is used. Furthermore, preferably, the coating step a) is a coating step in a fluid bed processor into which a solution or suspension (particularly solution) of ketamine hydrochloride and one or more excipients, such as hypromellose, on inert nuclei. The coating solution or suspension usually comprises, respectively consists of water and/or an alcohol. Preferably, the process temperature is between 30 and 60°C.

Preferably, step b) involves spray coating a coating solution containing the release control substance onto the coated inert cores of step a). The pulverization step is preferably carried out in a fluid bed processor. The fluid bed processor is preferably suitable for coating powders, particles, inert spheres, beads and tablets, and/or drying simultaneously. Preferably, the process temperature is between 30 and 60°C.

The solvent of the coating solution or suspension of step b) contains predominantly alcohol, ie the solvent used to dissolve the release control agent and optional additional excipients preferably contains 60% or more by weight, more preferably 70%. % or more by weight of alcohol. A mixture of ethanol and water is particularly preferred. Furthermore, ethylcellulose is preferably used as a release control agent. Additional excipients may include hydroxypropyl cellulose, talc, triethyl citrate, and other suitable pharmaceutical excipients.

The granules preferably have a weight average particle diameter (d50) of 50 to 1000 |im, in preferred embodiments 100 to 800 |im, in further embodiments 150 to 600 |im, as measured by sieve analysis, such as by means of control with Retsch Siebmaschine AS 300. The thickness of the release control layer is preferably in a range from 0.1 to 200 |im, preferably from 0.5 to 100 |im. Tablets with a combination of several of the above characteristics have been found to be particularly advantageous: they provide good clinical efficacy, largely due to providing an advantageous dissolution profile without the need to include an immediate release portion of ketamine. They can be broken or divided without affecting drug release from the tablet. There are no phenomena of rapid absorption of the dose.

The invention will be further described by means of exemplary embodiments with reference to the figure in which

Figure 1 shows the dissolution profiles of a tablet containing 20 mg of ketamine hydrochloride in 0.1 M HCl and of a tablet containing 20 mg of ketamine hydrochloride in 80:20 HCl/EtOH;

Figure 2a shows the geometric mean curves of (±)-ketamine after i.v. infusion. of 5 mg (within 0.5 h) and oral administration of modified-release tablets of 10, 20, 40 and 80 mg of ketamine according to the invention;

Figure 2b shows the geometric mean curves of (±)-norketamine after i.v. infusion. of 5 mg (within 0.5 h) and oral administration of modified release tablets of 10, 20, 40 and 80 mg of ketamine according to the invention.

examples

Example 1: Preparation of matrix controlled release tablets containing 20 mg of ketamine hydrochloride

Ketamine HCl, hydrogenated castor oil, microcrystalline cellulose and Aerosil 200 are sieved through a 600 µm sieve and mixed for 10 minutes.

Magnesium stearate is added to the mixture and further mixed for 2 minutes. Tablets with the composition outlined in the table above are pressed on a rotary machine with oblong punches.

Example 2: Preparation of multiparticulate tablets containing 20 mg of ketamine hydrochloride Step 1:

A spray solution is prepared from the following components:

A spray suspension is prepared by successively dissolving hypromellose and ketamine hydrochloride in a mixture of purified water and ethanol.

Sugar spheres (sucrose, particle size range (90%) 200 to 400 |im) are filled into a fluid bed processor with a bottom spray nozzle and preheated. The spray slurry is then sprayed onto the sugar spheres in the fluid bed processor, thereby preparing a plurality of sugar spheres having a layer of ketamine coated thereon. The coated sugar spheres are then sieved to remove agglomerates (vibrating sieve or equivalent).

Stage 2:

A coating suspension is prepared from the following components:

Hydroxypropyl cellulose is dissolved in water. Then ethylcellulose and ethanol are added to the solution. Finally, triethyl citrate and talc are added and the solution is stirred continuously.

A fluid bed processor is filled with the coated sugar spheres from step 1 and preheated. The coated solution prepared as above is sprayed onto the coated sugar spheres. The granules thus obtained are then sieved to remove agglomerates.

Stage 3:

The following components are dry blended to give a combination:

The resulting dry blend is then compressed into tablets.

Stage 4 (optional):

A tablet coating suspension is prepared from the following components:

31.6 kg of tablets are film-coated with the tablet coating suspension.

The dissolution profiles of the 20 mg tablets are in accordance with the present invention, as is evident from Figure 1. Dissolution profiles were measured using the USP Basket Method 1 at 37°C, 1000 mL 100 rpm in 0.1 M HCl and 80:20 HCl/EtOH.

Example 3: In vivo pharmacokinetics

A comparative bioavailability study of ketamine and norketamine was carried out after administration of a single dose of ketamine 10, 20, 40 and 80 mg modified-release tablets (as ketamine hydrochloride) according to the invention in the state of fasting and 5 mg of ketamine solution (as ketamine hydrochloride) for infusion. In the study, Cmax, Fabs, AUC0 were determined.” and Tmax. as previously described in vivo in healthy subjects.

Modified release tablets have been produced in analogy to example 2.

Goals

Consecutive, single-dose, open-label, five-treatment, five-period study with at least 7-day washout between study periods.

In the first treatment, all subjects received a single dose of 5 mg of (±)-ketamine solution for infusion over 30 min intravenously in the fasting state.

Single orally administered doses of (±)-ketamine modified-release tablets were administered in consecutively increasing doses of 10, 20, 40 and 80 mg with 240 ml of table water in the fasting state.

(±)-ketamine and (±)-norketamine were measured in serum, urine and feces

Number of subjects, main criteria for inclusion

• 15 analyzed

• age: 18 - 45 years

• gender: male and female

• ethnicity: Caucasian

• body mass index: > 18.5 kg/m2 and < 30 kg/m2

• good health as evidenced by the results of clinical examination, ECG, and laboratory testing, which were determined by the clinical investigator to not differ in a clinically relevant manner from the normal state

• heart rate between 50 and 90 bpm

• blood pressure between 140 and 100 systolic and 90 and 60 diastolic

• written informed consent

Sampling

Blood: blank, 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after intravenous administration and blank, 0, 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 h after oral administration

Urine: 0-24 h, 24-48 h and 48-72 h

Stool: 0-120 h

drug trial

Validated achiral LC-MS/MS method for (±)-ketamine and (±)-norketamine, performed in a GLP (good laboratory practice) certified laboratory

Pharmacokinetic results

The results are summarized in the following tables, where AUC ^ü -~ represents the area under the curve from zero extrapolated to infinity, Cmax. represents the maximum plasma concentration, Tmax. represents time to Cmax, Fabs represents absolute bioavailability, T1/2 represents apparent terminal half-life.

Table 1: Pharmacokinetic characteristics of (±)-ketamine after intravenous infusion (30 min) of 5 mg (±)-ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets

5 mg iv 10 mg 20 mg 40 mg 80 mg AUC ^ü . ^m ng xh/ml 59.9 13.2 13.5 9.73 27.1 21.9 75.6 48.3 178 145 Cmax. ng/ml 33.7 9.74 1.48 0.901 3.25 2.29 7.64 4.69 16.7 13.4 Tmax. H - 4.87 1.22 5.87 0.64* 6.00 0.76* 6.07 0.26* Fabs % - 11.5 8.09 11.0 8.57 15.9 9.53 *t 17.9 12.3*t T1/2 H 6.99 5.22 7.39 4.86 6.0964.98 8.44 1.54#t 8.89 1.42#t #vs. 5 mg IV, *vs 10 mg, vs 20 mg

Table 2: Pharmacokinetics of (±)-norketamine after intravenous infusion (30 min) of 5 mg (±)-ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets

5mg 10mg 20mg 40mg 80mg

AUCü-~ ng x h/ml 87.7 24.1 162 39.7 339 100 653 164 1620+731 Cmax. ng/ml 11.4 2.85 13.4 2.92 27.6 6.62 48.7 10.4 113 53.0 Tmax. H 0.93 0.32 4.72 1.02 5.33 0.77* 5.67 0.52* 6.10 0.60*ti T1/2 H 8.01 2.35 7.38 1, 63 7.74 3.09 8.25 2.70t 8.48 1.56* *vs 10 mg, vs 20 mg, vs 40 mg, p<0.05 (Wilcoxon test)

The maximum concentration (Cmax) and the time to maximum concentration (Tmax) were obtained directly from the measured concentration-time curves.

The area under the concentration-time curve (AUC0-t) was calculated from the data points measured from the time of administration to the last quantifiable concentration using the trapezoidal formula. AUC was evaluated up to the last sampling time above the limit of quantification and extrapolated to infinity to obtain AUCü-~ values.

The apparent terminal half-life (T1/2) was calculated by the following equation T-i/2=ln2/Xz. The terminal elimination rate constant (Xz) was evaluated from the terminal slope by log-linear regression analysis. Absolute bioavailability (Fabs) was calculated using the following equation

Fabs = AUCoral / AUCiv x doseiv / dose oral

Claims (8)

Yo. A modified release oral dosage form comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the ratio of the amount of ketamine released after 1 hour of in vitro dissolution of the dosage form at 37°C in an aqueous solution containing 20% by volume of ethanol based on the amount of ketamine released after 1 hour of in vitro dissolution of the dosage form at 37°C in an ethanol-free aqueous solution is less than about 2:1, when measured according to the USP basket method 1 in 0.1 M HCl at 100 rpm, where the dosage form is a matrix controlled release dosage form, or a multiparticulate controlled release, wherein in said matrix controlled release dosage form, ketamine is dissolved or dispersed in an inert matrix and released primarily by diffusion through the inert matrix once administered, and wherein said multiparticulate controlled release dosage form comprises granules containing a core comprising ketamine and a release control layer coated on the core. The modified release oral dosage form according to claim 1, wherein the ratio of the amount of ketamine released after 1 hour of in vitro dissolution of the dosage form at 37°C in an aqueous solution containing the 20% by volume ethanol based on the amount of ketamine released after 1 hour in vitro dissolution of the dosage form at 37°C in an ethanol-free aqueous solution is less than about 1.7:1, preferably less than 1.5:1, most preferably less than 1.2:1, when measured according to the USP 1 basket method in 0.1 M HCl at 100 rpm. The oral dosage form according to one of the preceding claims, which is a tablet. The oral dosage form according to one of the preceding claims, wherein the ketamine salt is ketamine hydrochloride and wherein the amount comprised in the oral dosage form is in the range of from 5 to 400 mg hydrochloride. of ketamine. The oral dosage form according to one of the preceding claims, wherein the dosage form is administered once or twice a day. The oral dosage form according to one of the preceding claims, for use in the treatment of neuropathic pain. The oral dosage form according to one of the preceding claims for use in the treatment of patients suffering from spinal cord injury, multiple sclerosis, cancer, immune mediated disorders, metabolic states such as diabetes, infection by shingles, HIV-related neuropathies, nutritional deficiencies. The oral dosage form according to one of the preceding claims for use in the treatment of depression in patients with depression and bipolar disorder who have not responded to antidepressants.